1. Field of the Invention
The present invention relates to forming conjugates of polymers and biologically active compounds, and to functional polymer precursors therefore.
2. Description of the Related Art
We have described in WO-A 2003/062290 (unpublished at the priority date hereof) the concept of taking a biologically active drug molecule and reacting it with a compound so as to functionalise it with an appropriate brominated moiety. The modified drug is capable of initiating an atom transfer radical polymerisation (ATRP) with monomers such as 2-methacryl-oyloxyethyl-2′-trimethylammonium ethyl phosphate inner salt. The compound 2-bromo-2-methyl propionic acid bromide is one such bromine-functionalising agent, the acid bromide portion reacting with any active hydroxyl group on the drug compound to produce a brominated analogue of a methacrylate moiety that has been shown to be eminently suitable for initiating ATRP (see works of Matyjaszewski, Armes and Haddleton). With this functionalising agent, this reaction is only possible in cases where the drug molecule and the 2-bromo, 2-methyl propionic acid bromide are both soluble in some organic solvent that is not reactive towards the acid bromide. In that specification we also describe a bromine-functionalising agent which is used to acylate an amine group, namely of a protein. The subject matter has a common priority date as claims of the present case and of example 4 herein.
It may be desirable to functionalise large biological entities such as proteins and antibodies with polymers. Roche and Schering-Plough both have on the market successful interferon-based products that have been modified by PEGylation of the biological entity. The attachment of polyethylene glycol chains to interferon has improved its plasma half-life (i.e. reduced the rate at which the body removes the antibody from the bloodstream), essentially by reduced renal clearance and lowering opsonisation (protein binding). It is of interest to modify such biological entities with other polymers, particularly those based on phosphorylcholine because of their enhanced haemocompatibility.
In U.S. Pat. No. 6,310,149 ATRP processes are described in which the initiator comprises a functional group which is a derivative of an organic acid. The acid may be a carboxylic acid or alternatively a phosphorus based acid or sulphonic acid. Examples of initiators are esters of various acids. Monomers which are polymerised include methylmethacrylate, styrene, benzylmethacrylate and 2-hydroxyethylmethacrylate. The polymerisations appear to be solvent-free, that is liquid monomer is the liquid medium for the polymerisation reaction.
Wang, J-S, et al in Polym. Mater. Sci. Eng. 73 (1995) 416 to 417 describe the use of bis-functional initiators for ATRP, whereby the residual group derived from the initiator may be used in subsequent reactions. Examples of end groups or precursors thereof are carboxyl groups, hydroxyl groups and cyano groups.